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Questions about use of cannabis in heart transplant patients (pre and post) are increasing due to its availability, legalization in some states, and media. What should patients know? Dr. Eileen Hsich, Medical Director of the Heart Transplant Program at Cleveland Clinic, Kathleen Faulkenberg PharmD, University of Kentucky, and Caroline Olt, MD, an internal medicine resident at Cleveland Clinic, co-authors of a recent paper on the topic discuss considerations such as the differences between types of cannabis, edibles vs. inhaled, frequency of usage, dependency, interactions with transplant medications, outcomes and current recommendations.

To learn more, read the article on Consult QD or the medical paper,"The growing dilemma of legalized cannabis and heart transplantation" in the Journal of Heart and Lung Transplantation.

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Cannabis Use in Heart Transplant Patients

Podcast Transcript

Announcer:
Welcome to Love Your Heart, brought to you by Cleveland Clinic's Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute. These podcasts will help you learn more about your heart, thoracic and vascular systems, ways to stay healthy, and information about diseases and treatment options. Enjoy.

Eileen Hsich, MD:
Hi, I'm Dr. Eileen Hsich. I am so glad you're here. I'm the Medical Director for Heart Transplantation at the Cleveland Clinic, and we've got the best podcast for you. We're going to talk about the growing dilemma of legalized cannabis and heart transplantation. Why? Why, you say? Oh, that's just because we recently published the article reviewing this subject in the Journal of Heart and Lung Transplantation, and guess what? I got all the participants in the podcast that are authors of that article. Today you're going to meet them. Dr. Caroline Olt, can you say hello?

Caroline Olt, MD:
Hi everyone. Thanks for listening.

Eileen Hsich, MD:
Oh, wonderful. Dr. Caroline Olt is originally from Pennsylvania. Is that correct?

Caroline Olt, MD:
Yes.

Eileen Hsich, MD:
We are so excited that she came to actually do her internal medicine residency at the Cleveland Clinic and is a wonderful addition to our program.

Eileen Hsich, MD:
I'm so excited that we have Dr. Kathleen Faulkenberg, the Cardiovascular Clinical Pharmacist at University of Kentucky Healthcare. You're from Kentucky, aren't you?

Kathleen Faulkenberg, PharmD:
I am.

Eileen Hsich, MD:
Dr. Caroline Olt, I think I'm going to let you take over from here and actually ask Dr. Faulkenberg and myself different questions. So go ahead.

Caroline Olt, MD:
All right, well, thank you, Dr. Hsich. My first question actually is for you. I was wondering if you could tell us a little bit more about the reason for writing this article and why it's so significant to the heart failure and transplant population.

Eileen Hsich, MD:
Yeah, this is actually really an important question. Cannabis is legalized in so many states and in different countries for medicinal recreational purposes that, of course, it comes up as a topic. In fact, actually when I just go to the hairdresser, I see it on the shop and it makes me think about, "Hmm. Is that oil really so bad?" Right? I mean, it's just very common now.

Eileen Hsich, MD:
The question really comes up, what are the rules of transplantation? Is this something of importance or not? Actually, when the International Society for Heart and Lung Transplantation updated their guidelines in 2016, there was very little data actually regarding the effects of cannabis, substance abuse and interactions with transplant immunotherapy. This topic actually was something that they really weren't prepared to actually address. They did have a statement though that said, "Patients who remain active substance abusers should not receive heart transplantation." Active substance abusers, but they were very careful to actually take the cannabis users and say, "Whoa, whoa, whoa, whoa, whoa. We do not know what to do with people who use cannabis. This is very controversial, and we will leave this decision to every transplant program across the world." What the result has been is that transplant policy varies from transplant center to transplant center, and may even vary within an institution based on an organ transplanted.

Eileen Hsich, MD:
I think it really is important to actually have more universal guidelines that are based on fact, and actually we need to synthesize the existing cannabis data as it relates to transplant in order to lay the foundation for what should or should not be the guidelines in the future for transplant patients. So that this way it isn't dependent on where you go, but really what we know.

Caroline Olt, MD:
Thank you. I think that really outlined why this is an important topic really well. Question next for Dr. Faulkenberg. What are some of the factors that contribute to the concern and controversy around cannabis and THC usage, especially within this specific population of heart transplant patients?

Kathleen Faulkenberg, PharmD:
Yeah. So I think even taking a step back and I think some of the general controversy with cannabis use is that where you get the cannabis from can be highly variable. So even taking a step back and saying, what are the different cannabinoids? So these are the different compounds within the marijuana plant itself. There's lots of variability, I think even within the plants and then amongst the plants. If you obtain a product, does it have more THC versus CBD versus, what is that ratio like? Because that's also going to have a potential impact on, are you getting more of the psychotropic effect versus are you getting more sort of this anti-inflammatory from the CBD component? I think there's even variability within the different plants themselves and the different concentration of these cannabinoids. Then you say, "Okay, I sell a different species that may have varying concentrations of these chemicals to a dispensary." Then they in and of themselves may say, "Oh, they can claim that this product does a certain thing, but really that's not regulated." So you can't-

Eileen Hsich, MD:
So what happens? So you and I could be growing cannabis and in our backyard, and I could have a stronger version. I could have a more potent plant than you? Is that possible?

Kathleen Faulkenberg, PharmD:
Yeah, that is possible. Then what part of that plant you give me could change it-

Eileen Hsich, MD:
What if I give you the stalk and I took the flower for myself? What would happen?

Kathleen Faulkenberg, PharmD:
We're going to have very different effects because I think what you'll see is that there's a lot more concentrated THC component or CBD or cannabinoids within the flowering part versus the stalk. But your question's exactly right. So how do we know how much we're getting? And we don't, because it's not regulated.

Eileen Hsich, MD:
Does it matter as a transplant patient if I like brownies and you like to smoke? What's the difference?

Kathleen Faulkenberg, PharmD:
Yeah. Typically, we see more of the psychotropic effects with THC, right? I think when you start to feel those effects or notice those effects can be very different, and then how much systemic exposure you're getting to the cannabinoids is going to differ too. If you're inhaling it, you're going to have a lot higher exposure a lot quicker, you're going to feel the effects sooner versus if you eat it. You have more variability with the absorption of it, and then you have a delayed onset for the peak. It can take a couple hours versus 30 minutes to an hour to feel effects.

Eileen Hsich, MD:
We can get high at different times. What about the fact, are you going to be worried about cancer if I happen to be somebody who likes to smoke a joint and you like to eat the brownie? I mean, is there a difference?

Kathleen Faulkenberg, PharmD:
I think that's another good question is that when you're inhaling and you're smoking a joint, let's say, then you're exposing yourself to other toxins or other impurities that are just sort of innately part of what you would get if you were to smoke tobacco. Same sort of carcinogens that we-

Eileen Hsich, MD:
Well that explains why the Canadians last year in the midst of the pandemic wrote a statement that they actually made a distinction, and they were not going to allow for transplant candidates to actually inhale cannabis. That makes sense. They were worried about the combustible products. Well, what happens if you use occasionally and I use all the time, I use it daily for goodness’ sake Dr. Faulkenberg, and what happens if you and I go into the bathroom and we actually have to have a sample of urine and I swear that I stopped about two weeks ago and you swear you stopped two weeks ago, but yours is clean and mine is not? Is that fair? Is that possible? I keep on telling you I really didn't use it that day. What happens? I'm the user that uses it daily and you're the user that rarely uses it. So you stopped in advance, but you really weren't using very much. Is it possible that I could be storing something in my body?

Kathleen Faulkenberg, PharmD:
Yeah. That's the other thing is that this is a lipophilic agent so it does deposit within the fatty tissues, the different metabolites.

Eileen Hsich, MD:
Are you calling me fat?

Kathleen Faulkenberg, PharmD:
No. Everybody has that. It's just different percentages. It's all about percentages. So no matter what that percentage, you still have some. Whether or not you'll have it in your hair or your skin or your urine, all the deposits, I think, will be a lot different depending on sort of the chronicity of usage. And so-

Eileen Hsich, MD:
How is that going to affect my transplant medicine? I don't care. I stopped using and it's all coming out of my system, and why are you bothering me?

Kathleen Faulkenberg, PharmD:
Right.

Eileen Hsich, MD:
My Prograf level or my cyclosporine levels when I actually have been using and then stop and start.

Kathleen Faulkenberg, PharmD:
Right. So you have of effects, I think, that we think about typically when you smoke marijuana or you ingest cannabis by eating it, but then if you're doing it chronically, you're always at steady state and you'll have some of those different cannabinoids seeping out through your fatty tissue storage. That actually has interplay on the different receptors within the body. You have CB1 and CB2 receptors. CB2 receptors typically are going to be more in your periphery so then you can have delayed gut motility, and of course, all of our agents that we use for anti-rejection medications are oral agents and rely on gut motility. All of them also rely on hepatic metabolism in order to be broken down into their metabolites and so-

Eileen Hsich, MD:
So this is going to affect my absorption of my meds.

Kathleen Faulkenberg, PharmD:
It could.

Eileen Hsich, MD:
Absorption. What about my drug levels? What's going to happen if I smoke a joint today or smoke it actually tomorrow? What happens to my drug levels?

Kathleen Faulkenberg, PharmD:
So, that's another good question is that it can cause variability within the drug levels. Because Prograf or Tacrolimus and Cyclosporine or Neoral are both going to be metabolized through our CYP enzymes within the liver and there are substrates for CYP3A4, you can potentially have increased systemic exposure if you're somebody who chronically uses marijuana or cannabis. And-

Eileen Hsich, MD:
That may change my drug level-

Kathleen Faulkenberg, PharmD:
Right? It could.

Eileen Hsich, MD:
I’m going to stop going to that dealer and I may have to go find another one.

Kathleen Faulkenberg, PharmD:
But in addition to that, it can potentially expose you to more adverse drug reactions and these medications can impact your kidneys, can impact your neurologic system, and so I think that there are some serious adverse effects that could potentially harm somebody for people who chronically use cannabis.

Eileen Hsich, MD:
Yeah. So actually there were some retrospective analysis that were for kidney transplantation, actually with Medicare patients demonstrating, for people who had cannabis use disorder, that there actually was a higher rate of rejection, death and even accidents. It impaired, there was a higher rate of accidents, car accidents. So yeah, unfortunately there was long-term consequences that seem to be in those that had an abuse problem.

Kathleen Faulkenberg, PharmD:
I think too, kind of going back to what you had said, a lot of these patients too may have potentially been smokers. So I think that there's, this could just be a high risk population in general, but yeah.

Eileen Hsich, MD:
Dr. Faulkenberg, I want to ask one more question. Do you know, we've been talking a whole lot about getting high, but actually what happens if I just want to feel good and I just actually use some CBD oil, or have any CBD ingestion, would that have any effect on my Tacrolimus levels, possibly, or my immunotherapy drug levels? Is that going to potentially affect it?

Kathleen Faulkenberg, PharmD:
Yeah, possibly. Again, it's not a controlled, we don't have any way of regulating that substance right now, so it's really hard to know exactly what you've ingested. I do think that there still is that risk for drug interactions. Of course our backbone anti-rejection medications are the lifeline for having good outcomes and graph survival post transplant, and so we really don't want to open up windows of opportunity for rejection. I think controlling that as much as we potentially can is really important. I think eliminating factors, especially the factors that you can control yourself, like not taking herbal supplements, including cannabis or cannabis products, should be one of those.

Eileen Hsich, MD:
Okay. I'm in agreement. Thank you.

Caroline Olt, MD:
Yeah. Thanks Dr. Faulkenberg and Dr. Hsich. Dr. Faulkenberg just to kind of follow up. I think we talked a little bit about this so far, but could you highlight what sort of the issues surrounding, continuing to use cannabis products are for patients after transplantation?

Kathleen Faulkenberg, PharmD:
Yeah, I think the biggest thing is going to be drug interactions and then, like I said earlier, I think that the drug interactions and having that window of opportunity where you're having either increased or decreased exposure, the levels, the variability of systemic exposure to our backbone anti-rejection agents is not something that I think that we're willing to take a risk at. So making sure that we have as consistent as possible levels for these narrow therapeutic index medications is extraordinarily important. So really I think that's probably the biggest complication posed by this, in addition to other things that Dr. Hsich has sort of alluded to as well. I think drug interactions is certainly the biggest from my perspective.

Caroline Olt, MD:
Great. Thank you so much. Another question I think for Dr. Hsich, what do you think are some of the misconceptions or myths that surround this issue?

Eileen Hsich, MD:
I think what I found the most interesting is that the question of whether or not cannabis is addictive. It is less addictive than substances like heroin and cocaine, it is even still less addictive than alcohol, but actually you can become addicted to cannabis. So it is a myth to say that this product is not addictive, and in fact, actually there is a disorder called cannabis use disorder that shares the same destructive properties as other addictions, with usage competing with other responsibilities in life, cravings, desires, and a lot of time spent recovering from the effects, failed efforts to quit or reduce amounts, and tolerance. Those are all the same findings you'd find when someone has an addiction for anything else. So kind of amazing. They actually have true definitions of who has recovered, who is just in the midst of recovery. I was really surprised to find out how much has been done in this subject.

Eileen Hsich, MD:
It's also important to recognize that cannabis users often have treatable, mental health disorders and polysubstance abuse. In one study of 61 transplant candidates referred for abuse and dependence, 42% had depression, 27% had anxiety and 31% had polysubstance abuse. Why is that important? Well, if you were anxious before and you were not helping you learn how to cope, you're going to have a lot of anxiety post-transplantation. I'm going to throw some steroids at you. You are going to have an emotional roller coaster, and we need to actually start addressing this and enabling the patients to have better coping skills then grabbing a joint or anything else that they would ingest, that actually can interfere with their immunotherapy. The fact that actually there's a very high percent of polysubstance abuse is very important because we actually don't allow other substances to actually, when abused, for those patients to be candidates for transplantation.

Caroline Olt, MD:
Thanks, Dr. Hsich. One more question for Dr. Faulkenberg. There have been some case reports of adverse cardiovascular events associated with cannabis like myocardial infarction and strokes, but there've been few research studies specifically for transplant, and these have been mostly retrospective analysis studies where they looked at patients with cannabis use disorder. Some of these case reports have found some association between cannabis use with non-adherence graph failure and death. But why do you think that research on this topic is so limited, especially when this is a subject that has a lot of public interest?

Kathleen Faulkenberg, PharmD:
Yeah. So again, from my perspective, I think that the reason that we have such limited studies using cannabis is because it's highly regulated. It's a schedule one substance, meaning that it has no acknowledged medicinal purpose. There's lots of regulations and potential barriers, and with that comes a higher cost of doing a study. Even though there is growing interest, we may see studies in the future, but I think right now that's probably one of the biggest barriers for doing research using cannabis products.

Eileen Hsich, MD:
That kind of limits all of our prospectives. So we're kind of the best, I think that gets done actually is the retrospective analyses. I think that when we limit it to things that are much more dangerous, like cannabis use disorder, we have noticed a whole, the bad sequela when it's actually casual usage that really varies a lot. Somebody could casually use weekly, somebody else can casually use every two to three days, and somebody else could use it once a year. So it's very hard unless the studies actually, when we're just checking a box and writing that someone has used, unless we actually quantify as we're collecting data, then the analysis really is often inadequate when we use cannabis use disorder that already kind of encompasses more serious because by definition you have to be a daily user and have abusive, addictive properties surrounding that. So I think that's very different, but it really has limited. It would be so nice to randomize patients, and I think you'd find a lot that would be willing to be randomized, but I actually, I don't think we can.

Eileen Hsich, MD:
So, Dr. Olt, we need to thank you for picking this amazing topic to review during your research time at the Cleveland Clinic. Did anything surprise you when you were researching this subject?

Caroline Olt, MD:
Yeah. I think kind of what we were just talking about, sort of how little research there is on this topic, especially because it is something that's becoming more prevalent and more important, was something that was surprising to me when we were doing the research for this study. I think it's something that we hopefully will be able to understand better in the future moving forward.

Eileen Hsich, MD:
I think that's very true. I hope that we continue to actually do more research and I don't think it will be prospective, but I think we can do a better job even in the retrospective arena. I think I'm going to leave with regards to just a few take home messages. Yes. Do not grow in your backyard unless it's actually legal. So don't do that. But with that, I'm going to also include a few more. So inhaled cannabis is more deleterious than edible cannabis because of the generation of combustible products and carcinogen similar to tobacco. So that is why the Canadians made a distinction, and I think that was a very wise choice. Number two, chronic cannabis usage can interfere with transplant immunotherapy, via drug interactions or reduced absorption with cannaboid hyperemesis syndrome. Is that true Dr. Faulkenberg?

Kathleen Faulkenberg, PharmD:
That is true.

Eileen Hsich, MD:
Okay. So we got two take home. Number three, cannabis addiction occurs with long-term use and is associated with underlying psychiatric disorders in history of polysubstance abuse. It is our obligation as medical providers to actually care for these patients. This is that true Dr. Olt?

Caroline Olt, MD:
Based on what we read, yeah.

Eileen Hsich, MD:
Okay. Cannabis use disorder. This is number four. Cannabis use disorder is the usage of cannabis. This is the definition for at least a year with history of intoxication, withdrawal, craving, risky behavior, social impairment and addiction. Okay. That really should be separated from the casual user. Last that I want to leave everyone with, is that casual cannabis usage needs to be distinguished, reiterating the same thing I just said, from the cannabis use disorder, which has been associated with non-compliance graft failure and death among transplant recipients based on large outcome data from kidney transplantation. So I think that what we've learned is actually that cannabis use disorder is a separate entity. It is an addiction like other substance addictions that represents a smaller percent of the patients and probably for the future, when we think about what needs to be addressed, is to take that addiction and treat it no differently than any other addiction and especially be concerned about the fact that it can interfere with their immunotherapy. With that everyone, I want to thank you for listening. I hope you have fun and enjoy your day.

Announcer:
Thank you for listening. We hope you enjoyed the podcast. We welcome your comments and feedback. Please contact us at heartatccf.org. Like what you heard? Subscribe wherever you get your podcasts or listen at clevelandclinic.org/loveyourheartpodcast.

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